A Randomized, Observer-Blind, Placebo-Controlled, Phase 2/3 Study to Assess the Safety, Efficacy, and Immunogenicity of a Recombinant Coronavirus-Like Particle COVID-19 Vaccine in Adults 18 Years of Age or Older

This Data Sharing Agreement authorises the use of information voluntarily provided to NHS Digital by individuals who have given permission to be contacted about potential participation in COVID-19 vaccine clinical trials. The data will be processed on behalf of the data controller, Medicago, by NHS Digital as a data processor for the purpose of supporting recruitment to participate in a COVID-19 vaccine trial being run by Medicago. Additionally, Syneos Health are also acting as a data processor on behalf of Medicago by managing the pre-screening website and passing details of potential participants on to the trial recruitment sites.

This Data Sharing Agreement authorises the use of information voluntarily provided to NHS Digital by individuals who have given permission to be contacted about potential participation in COVID-19 vaccine clinical trials. The data will be processed on behalf of the data controller, Medicago, by the data processor, NHS Digital, for the purpose of supporting recruitment to participate in a COVID-19 vaccine trial being run by Medicago.

The following provides background to the Permission to Contact (PtC) Service:

NHS Digital has agreed to work in partnership with the National Institute of Health Research (NIHR) to build and host a first of type online Permission to Contact (PtC) Service on nhs.uk where members of the public can register their details and give their permission to be contacted by researchers working on NIHR approved UK coronavirus vaccine trials about participating in those trials. This PtC Service, which is called “Sign Up to be Contacted about Coronavirus Vaccine Studies” on the nhs.uk website was launched as a national service on 20th July 2020.

This Service enables participants to:

• Provide permission for NHS Digital to share an individual’s details provided through the Service with the researchers undertaking COVID-19 UK vaccine trials for the purposes of researchers contacting that individual about taking part in those trials.

• Provide their permission to be contacted by NHS Digital about progress and outcomes from CV19 vaccine studies and in relation to the development of the PtC Service, including to inform them of opportunities to participate in other types of health research.

The data collected from individuals who sign up includes sufficient information to achieve the following purposes:

• Matching potentially eligible participants to eligibility criteria provided by the vaccine trials for their specific studies. This data will comprise of age, sex, geographic locations, type of employment, and a number health question e.g. about whether they have long-term health conditions.

• Providing relevant details of potentially eligible participants which have been obtained through the Service to researchers. This will allow the researchers to contact the participants with a view to discussing their taking part in a trial and if so, to obtain their further permission to take part in the trial.

• NHS Digital will provide access to the information obtained from individuals through the Service via the existing Data Access Request Service (DARS) process available to researchers working on UK COVID-19 vaccine trials sponsored by the National Institute of Health Research. The Service will only provide researchers with the data collected directly from individuals themselves through the Service.

The contact details will be used to invite potentially eligible individuals to undertake an eligibility assessment and, if eligible, to give informed consent to participate in this trial. NHS Digital, as data processor acting on behalf of Medicago, will be sending the email to eligible participants.

This request relates specifically to a vaccine trial. This is a Randomized, Observer-Blind, Placebo-Controlled, Phase 2/3 Study to Assess the Safety, Efficacy, and Immunogenicity of a Recombinant Coronavirus-Like Particle COVID-19 Vaccine in Adults 18 Years of Age or Older.

This Phase 2/3 study is a multi-portion design to confirm that the chosen formulation and dosing regimen of CoVLP (i.e. two doses of 3.75 µg CoVLP adjuvanted with AS03 given 21 days apart) has an acceptable immunogenicity and safety profile in adults 18 years of age or older, including those with significant comorbidities (Phase 2 portion). The efficacy of this CoVLP formulation in these same Study Populations will be assessed in the Phase 3 portion.

The Phase 2 portion is a randomized, observer-blinded, placebo-controlled study to evaluate the CoVLP formulation, compared to placebo, in subjects from the following three Study Populations:

1. Healthy adults 18-64

2. Healthy elderly adults* ≥ 65

3. Adults with significant comorbidities*≥ 18

In each Study Population, 306 subjects will be randomized 5:1 to receive the CoVLP formulation: placebo. All subjects will be followed for a period of 12 months after the last vaccination for durability of the immune responses, safety, and efficacy.

The Phase 3 portion is an event-driven, randomized, observer-blinded, placebo-controlled, 2-way cross-over design that will evaluate the efficacy and safety of the CoVLP formulation, compared to placebo, in the same Study Populations #1 - #3 presented above. Up to 30,000 subjects (across all participating countries) will be enrolled in a 1:1 ratio to receive the CoVLP formulation or placebo according to the following treatment sequences:

1. CoVLP formulation (period 1) Placebo (period 2)

2. Placebo (period 1) CoVLP formulation (period 2)

In the 2-way cross-over design, subjects who receive the CoVLP formulation in Period 1 will receive the placebo in Period 2, while subjects who receive the placebo in Period 1 will receive the CoVLP formulation in Period 2. Initiation of the cross-over design for subjects enrolled in the study will be dependent on the following overall study and subject-specific criteria:

1. When Emergency Use Authorization or Approval for the CoVLP formulation is granted by any Regulatory Agency(ies); and

2. When one or more authorized or approved COVID-19 vaccines become available for the subject in his/her country of recruitment; and

3. The subject has completed a minimum of 60 days in Period 1.

Emergency use authorization or approval will be pursued after the success criterion has been met for the primary efficacy endpoint of the Phase 3 portion. The primary efficacy endpoint will be evaluated once at least 160 laboratory-confirmed COVID-19 cases have been accumulated.

All subjects will be followed for efficacy and safety until 12 months after the last vaccination after the cross-over. The sero-status of all subjects will be assessed at the time of enrollment and at the time of the cross-over. Serum samples will be obtained from all subjects at 21 days after the second CoVLP vaccination so that a possible serologic correlate of protection can be evaluated once the primary efficacy outcome has been met and at later time points in the study. Only the 288 subjects (96 subjects from each Study Population) in the immunogenicity subset will be assessed for the persistence of the vaccine-induced humoral and cellular immune responses until 12 months after the last study vaccination.

In addition, a subset of 400 subjects from the United Kingdom (UK; UK-CMI subset) will be included in the exploratory evaluation of cell-mediated immunity (CMI) in Period 1 of the Phase 3 portion of the study.

The aim for this application is to recruit 3,000 participants. The initial mailout will aim for around four / five times the number of potential participants to be recruited and therefore the estimate is for up to 15,000 individuals to be contacted.

The above age ranges are as planned, but are subject to change depending on local decisions made in line with the deployed vaccine roll out in the UK. The age range may change for subsequent mail outs depending on the progress of the deployed vaccine roll out.

NHS Digital will extract a list of patients meeting the following criteria, where that criteria can be ascertained using the PtC registry:

INCLUSION CRITERIA:

• Study population #1: 18 - 64 years, good general health, pre-existing chronic disease allowed to participate if stable.

• Study population #2: 18 years+.

• Study population #3: 18 years of age or older with one or more co-morbid conditions that puts them at higher risk for severe COVID-19 disease, could include obesity, hypertension, diabetes, COPD, cardiovascular diseases, chronic kidney diseases or be immunocompromised.

EXCLUSION CRITERIA:

• All study populations: Pregnancy, vaccination within 14 days prior to visit 2, positive COVID-19 test. COVID-19 prophylaxis treatment.

• Populations #1 and #2: any chronic medical condition associated with elevated risk of severe outcomes of COVID-19, including obesity, diabetes, significant cardiovascular or respiratory diseases including asthma, chronic renal failure, bleeding disorders, chronic inflammatory or autoimmune conditions, immunosuppressive conditions (including HIV) and hypertension. Cancer treatment. Autoimmune diseases.

The inclusion and exclusion criteria noted above is based on the information provided by cohort members on the permission to contact dataset (where it can be obtained from this dataset), and is not collected from other NHS data sources. Some of the above inclusion and exclusion criteria will be used by the sites during the Screening phase.

NHS Digital will identify all individuals within the PtC dataset meeting the relevant criteria and will extract their names, email addresses and postcodes.

It is not known in advance how many individuals meeting the above criteria will have records in the PtC dataset. The number may be amended and the process may be repeated depending on the level of response. In the event of the trial not achieving a suitable balance in recruited participants, such as an uneven ratio of males to females, subsequent mail outs may restrict the required criteria to a greater degree than previously, for example, only requesting details for male participants as opposed to both males and females. This could encompass any part of the criteria, such as age, gender, ethnicity or location and various others, depending on how the recruitment progresses.

NHS Digital will write to the individuals in the subset inviting them to participate within the trial using ethically approved text provided by Medicago. The email will remind the individuals of the background of the permission to contact programme and give them the opportunity to state that they do not wish to be contacted again. The email will also direct volunteers to NIHR’s Be Part of Research website to access study information and regional contact information.

Individuals will not be contacted multiple times under this Agreement and NHS Digital will record the fact that the individuals have been contacted to ensure compliance with the maximum number of contacts outlined as part of consent. Furthermore, in order to ensure that NHS Digital are able to update the register with which participants are registered with an active trial, and therefore prevent them from being invited to any further trials, NHS Digital will be provided with regular updates of those registered participants who have consented. This sharing of information is built into the Permission to Contact signing up information and will also be added to the trial consent and participant information.

Syneos Health will supply individual recruitment sites with the IDs of those patients who have gone through the pre-screener in order to invite them for further screening. Individual trial recruitment sites will supply NHS Digital with details of those who have signed up to take part in their trial so that NHS Digital can suitably capture this information within the Permission To Contact registry. All data that flows to NHS Digital in this context falls under the controllership of Medicago. Once it is received at NHS Digital then NHS Digital become controller for that data in their existing role as controller of the Permission To Contact Registry.

Due to the nature of trial recruitment sites, they often only become confirmed as sites very close to recruitment, and so NHS Digital will leave the responsibility with the lead site / data controller to appointment data processors themselves under their own due diligence. This practice aligns with their obligations under GDPR as a data controller and the emphasis will be on the lead site / data controller to appoint appropriate data processors on their behalf. Ordinarily NHS Digital would carry out these checks, but attempting to do so for this service would cause unnecessary delay to the initial application, as well as potentially multiple and costly amendments thereafter. Therefore all recruitment sites / data processors and their processing activities will be covered under a suitable processing agreement between themselves and the lead site / data controller which does not require NHS Digital’s inclusion. Specific details of recruitment sites, such as key contact, location, will therefore not be made known to NHS Digital unless there is a specific reason to do so.

Additionally, Medicago have an appropriate data processing agreement in place with Syneos Health to support the recruitment into the trial under Medicago’s controllership

No other processing of the data will take place and the data will not be linked with information from any other sources.

Medicago will not have access to any of the data being disseminated by NHS Digital under this agreement.

The information from NHS Digital will be used to facilitate contact with individuals who are potentially eligible and who have indicated willingness to potentially participate in studies/trials of COVID-19 vaccines.

This is expected to result in individuals entering the trials screening process with a view to them participating in the trial with fully informed consent.

The main results from this trial are expected to inform development of a safe and effective multiple vaccine combination against COVID 19.

The primary benefit of using the data will be to recruit participants for the clinical study/trial in a manner which:

• Enables individuals to volunteer in advance to participate in COVID-19 vaccine trials as an alternative to other potentially more intrusive mechanisms, e.g. sharing data with researchers about individuals under section 251 consents or COPI notices, which although lawful is initially less transparent.

• Allows researchers to identify a suitable cohort and recruit them quickly into the vaccine trials – thus reducing the overall time to recruit into the trials and to accelerate the delivery of an effective vaccine to treat individuals to manage the COVID-19 outbreak and to save lives.

• Reduces burden on research staff in identifying and contacting potential clinical trial participants.

• Supports the Vaccines Taskforce objectives to drive forward, expedite and coordinate efforts to research and then produce a coronavirus vaccine and make sure one is made available to the public as quickly as possible.

Yielded Benefits is not a requirement for new applications.